Filer Journal of Cannabis Research (2020) 2:25 Journal of Cannabis https://doi.org/10.1186/s42238-020-00031-3 Research REVIEW Open Access Minnesota wild hemp: a crucial botanical source in early cannabinoid discovery Crist N. Filer1,2 Abstract Renewed and sustained Cannabis chemistry exploration was initiated by Roger Adams at the University of Illinois Chemistry Department with cooperation from the Treasury Department Narcotics Laboratory in the early 1940’s. This partnership and time investment by both parties made practical sense. Adams was able to explore natural products chemistry and the Narcotics Laboratory began to clarify the chemistry mysteries of Cannabis. Minnesota wild hemp, often viewed as just a roadside weed, was employed as the critical botanical source. Based on its widespread cultivation during World War II, this was also a very pragmatic decision. Although the unique Illinois – Washington D. C. collaboration lasted only a few short years (1939–1942), the stunning results included the isolation and extensive characterization of cannabidiol, the structure elucidation and total synthesis of cannabinol as well as the identification of the tetrahydrocannabinol structure as an intoxicating pharmacophore. Furthermore, this research well prepared many junior chemists for prolific careers in both academia as well as industry, inspired the discoveries of later Cannabis investigators and also provided a successful model of a productive academic-government partnership. Keywords: Cannabinoid, Federal Bureau of Narcotics, Minnesota wild hemp, Roger Adams, University of Illinois Background (Bridgeman and Abazia 2017).Itwouldtakeastrong Human cultivation of the genus Cannabis and exploit- and disciplined personality to navigate these changing ation of its useful materials easily dates back several thou- regulatory issues and advance Cannabis science. sand years (Russo 2007). Despite this long common Equally interestingly was the fact that a feral variety history, it is only in the last 80 years that significant pro- of Cannabis,Minnesotawildhemp,emergedasthe gress been made in understanding the fascinating details critical botanical source for the profound discoveries of Cannabis chemistry. Cannabis is the source of hun- in early cannabinoid chemistry. dreds of varied natural products and it is reported that 177 of these are the polyketide-terpene hybrids known History collectively as cannabinoids (Hanus et al. 2016). Natural The first isolation and characterization studies in the can- product isolation and characterization is an especially nabinoid area began in England with the work of Wood, challenging process involving human creativity along with Spivey and Easterfield in 1896 using Cannabis indica available resources. Further complicating progress in Can- (Wood et al. 1896). As would be the case for decades of nabis science by the mid-twentieth century was that the future Cannabis research, obtaining lipophilic cannabi- attitude in the United States toward Cannabis was quickly noids as crystalline solids from natural sources was a frus- changing. Once viewed in the late nineteenth century trating challenge. However, these workers eventually as a fashionable panacea, by the early 1940’s Canna- purified a substance as its acetate which upon hydrolysis bis was under increased scrutiny and near prohibition gave a phenolic compound that they named cannabinol. As so often happened in this natural products area, on- Correspondence: [email protected] 1 going progress in cannabinoid research was then abruptly PerkinElmer Health Sciences Inc., 940 Winter Street, Waltham, MA 02451, ’ USA stopped for decades. In the early 1930 s, Robert S. Cahn 2549 Albany St., Boston, MA 02118, USA again resumed work on cannabinol, isolating it from the © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Filer Journal of Cannabis Research (2020) 2:25 Page 2 of 5 same earlier source Cannabis indica.Cahnalsoprepared that time. With World War II looming and access to cannabinol derivatives, testing them with color forming valuable fibers from the Pacific rim curtailed, the gov- reactions and culminating in a close yet incorrect struc- ernment was actively growing large amounts of this ture prediction for cannabinol (Cahn 1933). However, sus- hardy fiber producing hemp in midwestern states includ- tained research and success on cannabinol and other ing Minnesota. cannabinoids waited for almost another decade and a The details regarding the Minnesota wild hemp har- unique Cannabis source as well as the creativity of an aca- vesting and initial large-scale processing are technically demic natural products chemist whose reputation was fascinating and partially outlined below, excerpted from already gaining momentum. the Experimental section of Adams’ first cannabinoid Harvard trained organic chemist Roger Adams began paper (Adams et al. 1940f): his extraordinary career at the University of Illinois Chem- istry Department in 1916. By 1939 Adams was already in “The hemp used in these experiments grew wild in mid-career, directing an extremely active group of a dozen Minnesota during the season of 1938. It was cut in or so graduate students producing a steady stream of sem- August, after flowering had begun but before seed inal papers in prestigious publications like the Journal of had “set” in the female tops. It was stored for 6 the American Chemical Society. Regarding natural prod- weeks in a room where a fan assured circulation of ucts, Adams fearlessly took on more challenging projects air in order to dry it completely. No molding oc- with the high risk of failure but also potentially large re- curred. The material was then beaten and shaken to ward. Many of these studies had important agricultural remove the course stems which amounted to about benefits. Relevant for this discussion, in 1939 Adams one third of the total dry weight. The stems were started another marathon natural products project which discarded and the relatively fine material that changed Cannabis chemistry forever. remained was extracted with 95% ethanol …”. In 1939, Adams was approached by the Treasury De- partment Bureau of Narcotics (today’s equivalent is the The above procedure was performed at the Treasury Drug Enforcement Administration) with an interesting Department Narcotics Laboratory in Washington D. C. proposition; namely, to carefully examine the still largely on a 40 kg hemp batch along with its large volume etha- unknown chemistry of Cannabis. Almost certainly, Ad- nol extraction process. The ethanol extracts were then ams was selected because of his celebrated success in concentrated to a small volume by an elaborate distilla- natural products and this proposal would have clearly tion system followed by petroleum ether dilution, several appealed to him for several reasons. First, the briefly ex- water washes and final distillation to yield about 100 g of plored Cannabis chemistry had been all but abandoned a purified red oil. This red oil, so frequently referred to years before and there were still many intriguing and un- in Adams’ many subsequent papers, was supplied to his answered questions. Secondly, the Treasury Department University of Illinois laboratory. While the Minnesota provided Adams with permission to work in this increas- wild hemp extraction operation was ongoing, Adams no ingly government supervised area. At that time, Canna- doubt was pouring over the earlier Robert S. Cahn bis was heavily regulated by the Marijuana Tax Act 1930’s publications as a valuable resource for developing (MTA) of 1937 which did not prohibit it but still im- his own technical strategy of cannabinoid isolation from posed expensive fines and possible imprisonment for vi- the Minnesota wild hemp red oil. Based on that re- olations, thereby strongly discouraging Cannabis use search, Adams was very aware there was little chance of (Pisanti and Bifulco 2017). Finally, the Narcotics Labora- directly crystallizing low melting cannabinoids them- tory offered to provide Adams with all the Cannabis raw selves from the red oil but often, higher melting deriva- material that he would need. Specifically, Minnesota wild tives of them could be. Here is where Adams first hemp (Cannabis sativa) was chosen as the botanical encountered an immediate and annoying technical prob- source for this renewed Cannabis research. Also known lem. In contrast to the earlier results of Cahn, Adams as “Ditch Weed,” this plant had been well described in could not obtain a crystalline cannabinoid acetate or p- an earlier classic botanical treatise (Oswald and Boss nitrobenzoate derivative from the Minnesota wild hemp 1918). This annual seed propagated Cannabis variety red oil. Devoting